Current Perspectives in NSAID-Induced Gastropathy

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most highly prescribed drugs in the world. Their analgesic, anti-inflammatory, and antipyretic actions may be beneficial; however, they are associated with severe side effects including gastrointestinal injury and peptic ulceration. Though several approaches for limiting these side effects have been adopted, like the use of COX-2 specific drugs, comedication of acid suppressants like proton pump inhibitors and prostaglandin analogs, these alternatives have limitations in terms of efficacy and side effects. In this paper, the mechanism of action of NSAIDs and their critical gastrointestinal complications have been reviewed. This paper also provides the information on different preventive measures prescribed to minimize such adverse effects and analyses the new suggested strategies for development of novel drugs to maintain the anti-inflammatory functions of NSAIDs along with effective gastrointestinal protection.

[1]  J. Wallace,et al.  Nitric oxide in mucosal defense: a little goes a long way. , 2000, Gastroenterology.

[2]  Barbara Sibbald,et al.  Rofecoxib (Vioxx) voluntarily withdrawn from market , 2004, Canadian Medical Association Journal.

[3]  A. Morelli,et al.  Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: role of tumour necrosis factor alpha. , 1994, Gut.

[4]  J. Vane,et al.  The fight against rheumatism: from willow bark to COX-1 sparing drugs. , 2000, Journal of physiology and pharmacology : an official journal of the Polish Physiological Society.

[5]  Marta L. Capone,et al.  Risk management profile of etoricoxib: an example of personalized medicine , 2008, Therapeutics and clinical risk management.

[6]  B. Peskar.  Role of leukotriene C4 in mucosal damage caused by necrotizing agents and indomethacin in the rat stomach. , 1991, Gastroenterology.

[7]  L. Lichtenberger.  Where is the evidence that cyclooxygenase inhibition is the primary cause of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal injury? Topical injury revisited. , 2001, Biochemical pharmacology.

[8]  K. Rokutan,et al.  NSAIDs induce both necrosis and apoptosis in guinea pig gastric mucosal cells in primary culture. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[9]  H. Davenport.  Salicylate damage to the gastric mucosal barrier. , 1967, The New England journal of medicine.

[10]  J. Robertson,et al.  Cerebral vasodilation and prostacyclin. The effects of aspirin and meclofenamate in vitro. , 1980, Journal of neurosurgery.

[11]  J. Wallace,et al.  Indomethacin-induced gastric injury and leukocyte adherence in arthritic versus healthy rats. , 1995, Gastroenterology.

[12]  P. Malfertheiner,et al.  Lansoprazole Fast Disintegrating Tablet: A New Formulation for an Established Proton Pump Inhibitor , 2003, Digestion.

[13]  L. Marzio,et al.  H2‐receptor antagonists are scavengers of oxygen radicals , 1994, European journal of clinical investigation.

[14]  A. Nguyen,et al.  Cyclooxygenase (COX-2) selective inhibitors. Any better than NSAIDs? , 2001, Canadian family physician Medecin de famille canadien.

[15]  Thomas R. Riley,et al.  A Randomized Double-blind Placebo-controlled Trial , 2004 .

[16]  C. Hawkey,et al.  Enhanced gastric mucosal leukotriene B4 synthesis in patients taking non-steroidal anti-inflammatory drugs. , 1993, Gut.

[17]  R. Hunt,et al.  Progress with proton pump inhibition. , 1992, The Yale journal of biology and medicine.

[18]  Deepak L. Bhatt,et al.  Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. , 2004, American heart journal.

[19]  T. Miller.  Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms. , 1983, The American journal of physiology.

[20]  D. Mikhailidis,et al.  THE EFECT OF NABUMETONE AND ITS PRINCIPAL ACTIVE METABOLITE ON IN VITRO HUMAN GASTRIC MUCOSAL PROSTANOID SYNTHESIS AND PLATELET FUNCTION , 1990 .

[21]  A. Macpherson,et al.  Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. , 1993, Gastroenterology.

[22]  C. Teixeira,et al.  Pharmacological Evaluation and Preliminary Pharmacokinetics Studies of a New Diclofenac Prodrug without Gastric Ulceration Effect , 2012, International journal of molecular sciences.

[23]  T. Brzozowski,et al.  Nitric oxide in gastroprotection by sucralfate, mild irritant, and nocloprost , 1994, Digestive Diseases and Sciences.

[24]  Vijay P. Singh,et al.  Licofelone--a novel analgesic and anti-inflammatory agent. , 2007, Current topics in medicinal chemistry.

[25]  R. DuBois,et al.  Cyclooxygenase, NSAIDs, and colorectal cancer , 1996, Journal of Gastroenterology.

[26]  P. Prasit,et al.  From indomethacin to a selective COX-2 inhibitor. Development of indolalkanoic acids as potent and selective cyclooxygenase-2 inhibitors. , 1997, Advances in experimental medicine and biology.

[27]  P Michael Ho,et al.  Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. , 2009, JAMA.

[28]  L. Mather,et al.  Effects of diclofenac in the rat tail ischaemia–reperfusion injury model of acute hyperalgesia , 2001, Pain.

[29]  R. S. Rogers,et al.  Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib). , 1997, Journal of medicinal chemistry.

[30]  S. Laufer,et al.  Licofelone, a novel 5-LOX/COX-inhibitor, attenuates leukocyte rolling and adhesion on endothelium under flow. , 2005, Biochemical pharmacology.

[31]  C. Thiemermann,et al.  Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[32]  D. Fitzgerald,et al.  Selective cyclooxygenase-2 inhibition by nimesulide in man. , 1998, The Journal of pharmacology and experimental therapeutics.

[33]  D. Volk,et al.  Insight into NSAID-induced membrane alterations, pathogenesis and therapeutics: characterization of interaction of NSAIDs with phosphatidylcholine. , 2012, Biochimica et biophysica acta.

[34]  J. Wallace,et al.  Anti-thrombotic effects of a nitric oxide-releasing, gastric-sparing aspirin derivative. , 1995, The Journal of clinical investigation.

[35]  J. Vane.  The mode of action of aspirin and similar compounds. , 1976, The Journal of allergy and clinical immunology.

[36]  K. Wu,et al.  Cyclooxygenase 2 induction: molecular mechanism and pathophysiologic roles. , 1996, The Journal of laboratory and clinical medicine.

[37]  L. Laine.  The role of proton pump inhibitors in NSAID-associated gastropathy and upper gastrointestinal symptoms. , 2003, Reviews in gastroenterological disorders.

[38]  T. Watanabe,et al.  Effect of prostaglandin E2 on thermoresponsive neurones in the preoptic and ventromedial hypothalamic regions of rats. , 1988, The Journal of physiology.

[39]  L. G. García Rodríguez,et al.  Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population. , 2008, Journal of the American College of Cardiology.

[40]  F. Coluzzi,et al.  COX-2 inhibitors: pharmacological data and adverse effects. , 2005, Minerva anestesiologica.

[41]  R. Playford,et al.  Co-administration of the health food supplement, bovine colostrum, reduces the acute non-steroidal anti-inflammatory drug-induced increase in intestinal permeability. , 2001, Clinical science.

[42]  D. Graham,et al.  Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. , 1999, JAMA.

[43]  M. Konstam,et al.  Current perspective on the cardiovascular effects of coxibs. , 2002, Cleveland Clinic journal of medicine.

[44]  E. Topol,et al.  Risk of cardiovascular events associated with selective COX-2 inhibitors. , 2001, JAMA.

[45]  J. Pelletier,et al.  Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs , 2003, Annals of the rheumatic diseases.

[46]  K. Takeuchi,et al.  Lack of Gastric Toxicity of Nitric Oxide-Releasing Indomethacin, NCX-530, in Experimental Animals , 2001, Digestive Diseases and Sciences.

[47]  L. Laghi,et al.  Activity and potential role of licofelone in the management of osteoarthritis , 2007, Clinical interventions in aging.

[48]  A. Barkun,et al.  Omeprazole Compared with Misoprostol for Ulcers Associated with Nonsteroidal Antiinflammatory Drugs , 1998 .

[49]  N. Maskrey,et al.  NSAIDs, gastroprotection and cyclo‐oxygenase‐II‐selective inhibitors * , 2003, Alimentary pharmacology & therapeutics.

[50]  A. Barkun,et al.  Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. , 1999, The New England journal of medicine.

[51]  T. Tsuchiya,et al.  Membrane permeabilization by non-steroidal anti-inflammatory drugs. , 2004, Biochemical and biophysical research communications.

[52]  L. Marnett,et al.  Design of selective inhibitors of cyclooxygenase-2 as nonulcerogenic anti-inflammatory agents. , 1998, Current opinion in chemical biology.

[53]  A. Grundy,et al.  Ileal stricturing after long-term indomethacin treatment. , 1986, Postgraduate medical journal.

[54]  R. Playford,et al.  Bovine colostrum is a health food supplement which prevents NSAID induced gut damage , 1999, Gut.

[55]  V. Shah,et al.  The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis , 2005, Hepatology.

[56]  Lise,et al.  Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. , 2000, The New England journal of medicine.

[57]  A. Price,et al.  Mitochondrial damage: a possible mechanism of the “topical” phase of NSAID induced injury to the rat intestine , 1997, Gut.

[58]  E. Antman,et al.  ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use , 2008, The American Journal of Gastroenterology.

[59]  Patrice Cacoub,et al.  Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. , 2006, The New England journal of medicine.

[60]  C. Hawkey,et al.  Esomeprazole provides effective control of NSAID-associated upper GI symptoms in patients continuing to take NSAIDs , 2003 .

[61]  U. Bandyopadhyay,et al.  A Novel Antioxidant and Antiapoptotic Role of Omeprazole to Block Gastric Ulcer through Scavenging of Hydroxyl Radical* , 2003, The Journal of Biological Chemistry.

[62]  R. Makuch,et al.  Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. , 2000, JAMA.

[63]  J. Wallace.  Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years. , 1997, Gastroenterology.

[64]  Li Hai,et al.  Design, synthesis and biological evaluation of brain-specific glucosyl thiamine disulfide prodrugs of naproxen. , 2011, European journal of medicinal chemistry.

[65]  L. Lichtenberger,et al.  Recombinant human lactoferrin prevents NSAID‐induced intestinal bleeding in rodents , 2005, The Journal of pharmacy and pharmacology.

[66]  C. Ioannides,et al.  A retrospective study of the molecular toxicology of benoxaprofen. , 1990, Toxicology.

[67]  N. Davies,et al.  NO‐naproxen vs. naproxen: ulcerogenic, analgesic and anti‐inflammatory effects , 1997, Alimentary pharmacology & therapeutics.

[68]  E. Hahn,et al.  Duodenal mucosal protection by bicarbonate secretion and its mechanisms. , 2004, Journal of physiology and pharmacology : an official journal of the Polish Physiological Society.

[69]  E. Woolf,et al.  Determination of rofecoxib, a cyclooxygenase-2 specific inhibitor, in human plasma using high-performance liquid chromatography with post-column photochemical derivatization and fluorescence detection. , 1999, Journal of chromatography. B, Biomedical sciences and applications.

[70]  J. Wallace,et al.  Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy , 1992, Inflammation.

[71]  V. Wong,et al.  Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. , 2002, The New England journal of medicine.

[72]  A. Gigante,et al.  Non-Steroidal Anti-Inflammatory Drugs and Gastroprotection with Proton Pump Inhibitors , 2012, Clinical Drug Investigation.

[73]  J. Senior,et al.  Misoprostol Reduces Serious Gastrointestinal Complications in Patients with Rheumatoid Arthritis Receiving Nonsteroidal Anti-Inflammatory Drugs , 1995, Annals of Internal Medicine.

[74]  K. Ms,et al.  The Role of Cyclooxygenase in Gastric Mucosal Protection , 2005, Digestive Diseases and Sciences.

[75]  B. Bannwarth,et al.  Pharmacological aspects of chiral nonsteroidal anti‐inflammatory drugs , 1990, Fundamental & clinical pharmacology.

[76]  J. Falgueyret,et al.  Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX‐2 inhibitor , 1997, British journal of pharmacology.

[77]  P. Collins,et al.  Synthesis and Biological Evaluation of the 1,5-Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors: Identification of 4-(5-(4-Methylphenyl)-3- (trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (SC-58635, Celecoxib). , 2010 .

[78]  S. Goldhaber,et al.  Gastrointestinal complications of dual antiplatelet therapy. , 2006, Circulation.

[79]  G. Nuki.  Pain control and the use of non-steroidal analgesic anti-inflammatory drugs. , 1990, British medical bulletin.

[80]  Deepak L. Bhatt,et al.  Omeprazole and clopidogrel: Should clinicians be worried? , 2010, Cleveland Clinic Journal of Medicine.

[81]  Stolte,et al.  Changes in Helicobacter pylori‐induced gastritis in the antrum and corpus during and after 12 months of treatment with ranitidine and lansoprazole in patients with duodenal ulcer disease , 1998, Alimentary pharmacology & therapeutics.

[82]  S. Laufer,et al.  The mechanism of action of the new antiinflammatory compound ML3000: inhibition of 5-LOX and COX-1/2 , 2002, Inflammation Research.

[83]  A. Stephenson,et al.  Inhibition of Prostaglandin Synthesis by Indomethacin Augments the Renal Vasodilator Response to Bradykinin in the Anesthetized Dog , 1978, Circulation research.

[84]  Punit Kaur,et al.  The structural basis for the prevention of nonsteroidal antiinflammatory drug-induced gastrointestinal tract damage by the C-lobe of bovine colostrum lactoferrin. , 2009, Biophysical journal.

[85]  J. Dent,et al.  Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. , 2000, Gastroenterology.

[86]  P. Lipsky,et al.  Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects. , 1998, Arthritis and rheumatism.

[87]  Sujata Sharma,et al.  Structural and binding studies of C-terminal half (C-lobe) of lactoferrin protein with COX-2-specific non-steroidal anti-inflammatory drugs (NSAIDs). , 2010, Archives of biochemistry and biophysics.

[88]  P. O’Brien,et al.  Effect of nonsteroidal anti-inflammatory drugs on LFA-1 and ICAM-1 expression in gastric mucosa. , 1994, The American journal of physiology.

[89]  F. Lovejoy.  Aspirin and acetaminophen: a comparative view of their antipyretic and analgesic activity. , 1978, Pediatrics.

[90]  M. Gilard,et al.  Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin , 2006, Journal of thrombosis and haemostasis : JTH.

[91]  J. Wallace,et al.  NO‐naproxen modulates inflammation, nociception and downregulates T cell response in rat Freund's adjuvant arthritis , 2000, British journal of pharmacology.

[92]  S. C. Wang,et al.  Temperature-sensitive neurons in preoptic-anterior hypothalamic region: actions of pyrogen and acetylsalicylate. , 1968, The American journal of physiology.

[93]  W. Saris,et al.  Recombinant human lactoferrin ingestion attenuates indomethacin-induced enteropathy in vivo in healthy volunteers , 2003, European Journal of Clinical Nutrition.

[94]  T. Schubert,et al.  Duodenal and Gastric Ulcer Prevention with Misoprostol in Arthritis Patients Taking NSAIDs , 1993, Annals of Internal Medicine.

[95]  T. Durand,et al.  The metabolic effects of inhibitors of 5-lipoxygenase and of cyclooxygenase 1 and 2 are an advancement in the efficacy and safety of anti-inflammatory therapy. , 2003, Prostaglandins & other lipid mediators.

[96]  A. Qandil.  Prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), More Than Meets the Eye: A Critical Review , 2012, International journal of molecular sciences.

[97]  Dominique Mottier,et al.  Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. , 2008, Journal of the American College of Cardiology.

[98]  K. Hahm,et al.  Rescue strategies against non‐steroidal anti‐inflammatory drug‐induced gastroduodenal damage , 2009, Journal of gastroenterology and hepatology.

[99]  D. Hahn,et al.  Effects of suprofen and other prostaglandin synthetase inhibitors in a new animal model for myometrial hyperactivity. , 1982, Prostaglandins.

[100]  C. Hawkey,et al.  Dual COX inhibition and upper gastrointestinal damage. , 2003, Current pharmaceutical design.

[101]  P. Mcgeer,et al.  Cardiovascular events and COX-2 inhibitors. , 2001, JAMA.

[102]  Sherri C. Young,et al.  Investigation of anticholinergic and non‐steroidal anti‐inflammatory prodrugs which reduce chemically induced skin inflammation , 2012, Journal of applied toxicology : JAT.

[103]  F. Coluzzi,et al.  Oxycodone. Pharmacological profile and clinical data in chronic pain management. , 2005, Minerva anestesiologica.

[104]  L. Crofford,et al.  Effects of Selective Cyclooxygenase-2 Inhibition on Vascular Responses and Thrombosis in Canine Coronary Arteries , 2001, Circulation.

[105]  J. Wallace.  Hydrogen sulfide-releasing anti-inflammatory drugs. , 2007, Trends in pharmacological sciences.

[106]  M. Maftouh,et al.  Structure and stereochemistry of the active metabolite of clopidogrel. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[107]  K. Seibert,et al.  Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[108]  I. Rodger,et al.  Selective cyclooxygenase-2 inhibitors as potential therapeutic agents for inflammatory diseases. , 1997, Advances in experimental medicine and biology.

[109]  C. Wilder-Smith,et al.  Esomeprazole 40 mg Provides Improved Intragastric Acid Control as Compared with Lansoprazole 30 mg and Rabeprazole 20 mg in Healthy Volunteers , 2004, Digestion.

[110]  T. Singh,et al.  Preparation and characterization of the N and C monoferric lobes of buffalo lactoferrin produced by proteolysis using proteinase K , 1999, Journal of Dairy Research.

[111]  W. Ray,et al.  Nonsteroidal anti-inflammatory drugs and the incidence of hospitalizations for peptic ulcer disease in elderly persons. , 1995, American journal of epidemiology.

[112]  Peter C. Austin,et al.  A population-based study of the drug interaction between proton pump inhibitors and clopidogrel , 2009, Canadian Medical Association Journal.

[113]  Thongchai Korsuntirat.  Non-steroidal antiinflammatory drugs (NSAIDs) (ยาลดการอักเสบที่ไม่ใช่เสตียรอยด์) , 2010 .

[114]  G. Tildesley,et al.  Prevention of gastroduodenal damage induced by non-steroidal anti-inflammatory drugs: controlled trial of ranitidine. , 1988, BMJ.

[115]  J. Vane,et al.  Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. , 1971, Nature: New biology.

[116]  A. Sparatore,et al.  H(2)S-Releasing Aspirin Protects against Aspirin-Induced Gastric Injury via Reducing Oxidative Stress , 2012, PloS one.

[117]  J. Wallace,et al.  ML 3000 reduces gastric prostaglandin synthesis without causing mucosal injury. , 1994, European journal of pharmacology.

[118]  F. Chan,et al.  Guidelines for Prevention of NSAID-Related Ulcer Complications , 2009, The American Journal of Gastroenterology.

[119]  K. Rainsford,et al.  Ibuprofen: from invention to an OTC therapeutic mainstay , 2013, International journal of clinical practice. Supplement.

[120]  Simon C Watkins,et al.  Targeting nitric oxide (NO) delivery in vivo. Design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-alpha-induced apoptosis and toxicity in the liver. , 1997, Journal of medicinal chemistry.

[121]  M. Wolfe,et al.  Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. , 1999, The New England journal of medicine.

[122]  G. Harewood.  Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. , 1999, The New England journal of medicine.

[123]  L. Laine.  Proton pump inhibitor co-therapy with nonsteroidal anti-inflammatory drugs--nice or necessary? , 2004, Reviews in gastroenterological disorders.

[124]  Deepak L. Bhatt,et al.  Clopidogrel with or without omeprazole in coronary artery disease. , 2010, The New England journal of medicine.

[125]  D. Glavač,et al.  Cyclooxygenase in normal human tissues – is COX-1 really a constitutive isoform, and COX-2 an inducible isoform? , 2008, Journal of cellular and molecular medicine.

[126]  E. Antman,et al.  Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials , 2009, The Lancet.

[127]  D. DeMets,et al.  Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial , 2008, The Lancet.

[128]  Charles J. Kahi,et al.  ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use , 2010, The American Journal of Gastroenterology.

[129]  T. Burnakis.  Cardiovascular events and COX-2 inhibitors. , 2001, JAMA.

[130]  P. K. Moore,et al.  Pharmacology and potential therapeutic applications of nitric oxide‐releasing non‐steroidal anti‐inflammatory and related nitric oxide‐donating drugs , 2002, British journal of pharmacology.

[131]  R. DuBois,et al.  Colorectal cancer and nonsteroidal anti-inflammatory drugs. , 1997, Advances in pharmacology.

[132]  U. Marathi,et al.  Association of phosphatidylcholine and NSAIDs as a novel strategy to reduce gastrointestinal toxicity. , 2009, Drugs of today.

[133]  F. Coluzzi,et al.  Pharmacological profile and clinical data in chronic pain management , 2005 .

[134]  K. Seibert,et al.  Role of inducible cyclooxygenase (COX-2) in inflammation. , 1994, Receptor.

[135]  T. Schnitzer,et al.  The safety profile, tolerability, and effective dose range of rofecoxib in the treatment of rheumatoid arthritis. Phase II Rofecoxib Rheumatoid Arthritis Study Group. , 1999, Clinical therapeutics.

[136]  G. Falk,et al.  Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial , 2000, Alimentary pharmacology & therapeutics.

[137]  B. Martin,et al.  Effect of the Clopidogrel–Proton Pump Inhibitor Drug Interaction on Adverse Cardiovascular Events in Patients with Acute Coronary Syndrome , 2012, Pharmacotherapy.

[138]  M. Koch.  Non-steroidal anti-inflammatory drug gastropathy: clinical results with misoprostol. , 1999, Italian journal of gastroenterology and hepatology.

[139]  T. Brzozowski,et al.  Implications of nitric oxide in the action of cytoprotective drugs on gastric mucosa. , 1993, Journal of Clinical Gastroenterology.

[140]  C. Scarpignato,et al.  Prevention and treatment of non-steroidal anti-inflammatory drug-induced gastro-duodenal damage: rationale for the use of antisecretory compounds. , 1999, Italian journal of gastroenterology and hepatology.

[141]  L. Lichtenberger.  The hydrophobic barrier properties of gastrointestinal mucus. , 1995, Annual review of physiology.

[142]  C. Sakamoto,et al.  The Role of Cyclooxygenase in Gastric Mucosal Protection , 2005, Digestive diseases and sciences.

[143]  M. Suresh,et al.  Dinitroglyceryl and diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of aspirin, indomethacin and ibuprofen: synthesis, biological evaluation and nitric oxide release studies. , 2009, Bioorganic & medicinal chemistry letters.

[144]  C. Hawkey,et al.  Nonsteroidal anti-inflammatory drug gastropathy. , 2000, Gastroenterology.

[145]  K. Seibert,et al.  Cyclooxygenase-2 inhibitors: a new class of anti-inflammatory agents that spare the gastrointestinal tract. , 1996, Gastroenterology clinics of North America.

[146]  L. Welage,et al.  Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases. , 2000, Journal of the American Pharmaceutical Association.

[147]  J. W. Griffin,et al.  Effect of ranitidine gastroduodenal mucosal damage induced by nonsteroidal antiinflammatory drugs , 1989, Digestive Diseases and Sciences.

[148]  R. Mannucci,et al.  Gastrointestinal safety of nitric oxide-derived aspirin is related to inhibition of ICE-like cysteine proteases in rats. , 1999, Gastroenterology.